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MRC/BBSRC GCRF Networks for Vaccine R&D: At the open call launch meeting on 14 October 2016, participants identified potential science areas of focus for Networks. Groups are now working on EOIs, however the MRC and BBSRC are not mandating that the EOIs stay fixed on these themes; if other groups/themes emerge, applicants can develop and submit their ideas – if you wish to be added to this document, please email [email protected] and provide a title, summary, and key contact. To support Network formation the potential areas are listed below and where provided, further details including contacts are given in Annex I. Please note this document is live – please check for further updates if information is missing Contents Antibodies for therapy and prevention of infectious disease 3 Antigen design and validation 4 Bacterial vaccinology 5 Comparative immunology of vaccines in low and middle income countries (LMICs) 6 Correlates of protection in vaccine development (comparative immunology) 7 Development of a trivalent vaccine for cattle papilloma, diarrhoea and rabies viruses 8 Emerging infections – pathogen biology and evolution 9 Formulation and stability (inc. cold chain), and modes of vaccine delivery 10 Human challenge models 11 Immune responses to enteric vaccines (inc. underperformance of rotavirus vaccine) Immunogen design 12 Immunogen design 13 1 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC Network to define methodologies for early phase and pre-licensure impact of candidate vaccines on transmission of target infections (herd effects) 14 In vivo animal models 15 Iterative vaccine development for complex neglected intracellular pathogens (TB, Leishmania, Burkholderia) 16 Structural vaccinology 17 Successful vaccination against parasitic helminths: a global approach through targeting immunomodulators 18 Systems Biology Network 19 Understanding the human host: the role of age, diet, co-morbidities, ethnicity, and vaccines throughout the life course (including maternal immunisation) 20 Vaccines for chronic diseases 21 Mixing Infectious Disease, Inflammation and Vaccines (MIDIV): Effects of co-challenges on immune responses 22 2 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC ANNEX I 1. Antibodies for therapy and prevention of infectious disease Network Abstract: From the early development of diphtheria and tetanus antitoxins, passive immunisation has been an important means of controlling infection. It remains vital for some diseases like rabies, in resource-poor regions of the world. Whilst immune serum is still widely used, the possibility of using monoclonal antibodies has attracted increasing interest. Palivizumab is a commercial product for prevention of respiratory syncytial virus, a range of broadly neutralising monoclonal antibodies (eg VRC01) are in clinical trial for HIV, and the recent use of the ZMapp cocktail of three antibodies during the 2014 Ebola outbreak, are illustrations of the emerging field. Monoclonal antibody based treatments have the advantages of being highly specific and potent, a long history of safe use in humans and providing immediate protection in patients irrespective of their immune status. The disadvantages lie in their availability, cost of manufacture and the potential for pathogen escape. This Network group would work to advance the field in a number of areas, including: 1. Identification of current and emerging infections that are amenable to antibody based prevention. 2. Neutralising epitope discovery for major pathogens. 3. Molecular modelling of broadly neutralising mAb / antigen interactions. 4. Identification of new mAb candidates for bacterial, viral and fungal diseases that are broadly neutralising and highly potent. 5. Antibody engineering to enhance functionality – antigen binding and specificity, effector functionality, pharmacokinetics, pharmacodistribution 6. Design of antibody combinations to provide broad protection against prevalent strains and prevent escape emergence. 7. Antibodies as immunomodulators for antigen delivery. 8. Animal model development for human antibody therapies. 9. Understanding the immune response to therapeutic mAbs. 10. Design of clinical trials to facilitate and accelerate mAb based interventions, particularly those involving combination products. 11. Manufacturing solutions for mAbs to enable commercial development, particularly for diseases prevalent in LMIC. 12. Potential roles for mAb based treatments in the early rapid response to emerging infections. Contact: Professor Julian Ma St George’s University London [email protected] 3 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 2. Antigen design and validation Network Abstract: Contact: 4 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 3. Bacterial vaccinology Network Abstract: Globally, bacteria cause millions of deaths each year in animals and humans. As antimicrobial resistance increases, this number is set to rise with devastating personal and economic costs. Much of the burden of bacterial-driven disease occurs in low and middleincome countries (LMICs). While these bacterial infections can occur as epidemics, they are more often endemic in nature. Furthermore, bacterial infections are intrinsically difficult to diagnose and this is exacerbated due to a lack of health-care infrastructure and diagnostic facilities in LMICs, and therefore are both under-recognised as a public health problem and difficult to treat. Where diagnosis is possible, effective treatment is often compromised by the growing presence of antimicrobial resistance. Such factors make bacterial infections particularly suitable to prevention through the development of new vaccines. Promoting the development and use of vaccines in humans and animals to save lives and reduce unnecessary antibiotic use was a specific recommendation of the recent O’Neill report on antimicrobial resistance. Moreover, the combination of relative conservation of bacterial antigens, availability of proven, existing vaccine strategies (e.g. glycoconjugate, live attenuated and whole cell inactivated vaccines) and the potential of new technologies (e.g. outer membrane vesicles and protein glycan coupling technology, viral vectors and RNA vaccines) suggests that bacterial infections represent ‘low-hanging fruit’ for vaccine development. Most excitingly, the same vaccine technology platforms are applicable to a range of bacterial pathogens, and there is huge potential for exploitation of this from encouraging the cross-fertilisation of ideas between scientists working on a range of bacterial pathogens. Whilst the value of such interactions is clear, what is lacking currently is a network to enable a range of stakeholders to engage with and make use of this expertise to target existing threats or to enable a rapid response to emerging bacterial pathogens. Considerable strength and depth is already present in the UK in disciplines related to vaccinology to bacterial infections, including immunology, epidemiology, microbiology, structural biology, genomics and systems biology approaches. However, experts in these various fields currently have no dedicated forum through which to interact and accelerate the research and development required for new anti-bacterial vaccines. Interactions between interested parties in bacterial vaccinology in academia and industry (including small biotech operations as well as large vaccine manufacturers), and in medical and veterinary fields (necessary for a One Health approach) could be significantly improved. The proposed network is the forum that will enable this to happen. In the context of vaccines for LMICs, researchers in the UK already have links to a large number of sites in LMICs where studies on endemic bacterial diseases are ongoing and where vaccine field trials could be conducted. Collectively, these factors make the establishment of a UK bacterial vaccines network a timely and necessary imperative to harness the existing expertise in our country for the advancement of bacterial vaccines for use in LMIC. Without such a network, there is a real risk that progress made through the UK science base in vaccinology will not accelerate, and will be consigned to the slow lane at the time when it is most needed to provide a real challenge to the spread and threat of anti-microbial resistance. Contact: Calman MacLennan University of Oxford [email protected] 5 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 4. Comparative immunology of vaccines in low and middle income countries (LMICs) Network Abstract: Contact: 6 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 5. Correlates of protection in vaccine development (comparative immunology) Network Abstract: The 2014 ‘MRC Review of Vaccines Research’ led by IIB had highlighted the following key point: ‘Immune correlates of protection – Advancing research and development (R&D) of novel vaccines that elicit a protective immune response will require identification of the differences between general immune responses to a pathogen or vaccine, and the response that confers protective immunity for the long-term [which might be pathogen and host specific]. Studying individuals who show naturally acquired immunity to disease (e.g. sex workers in Kenya with immunity to HIV) would provide insights into true correlates of protection and identify potential candidate antigens’. The vaccine development bottleneck(s) this network seeks to address Investigators, producers, regulators and healthcare policy-makers developing new vaccine programmes have in the past attached considerable importance to ‘correlates of protection’ in trial evaluation. These have most typically been neutralizing antibody titres deduced to offer a correlate of in vivo protective efficacy. The ability of an immunization regimen to attain the required value may have profound impact on ‘stop-go’ decisions. We urgently need a more creative approach to assessing endpoints and protection, whether in human challenge studies or in field vaccine trials. In an age of vaccine strategies to confront diverse, emerging pathogens and a need to generate a shortened timeline to vaccine trials and evaluation, there is an appreciation that a new toolbox is needed. In many cases, the ability to assume a defined, pertinent correlate of protection may require detailed build-up of knowledge on the pathophysiology/immunology of the specific disease – which are the protective antigens to which immunity must be assessed? What is the clinical spectrum of response to exposure and, thus, which protective endpoint is relevant? Is there an issue of crossreactive baseline immunity to related microbial species? Is there an issue of baseline, asymptomatic exposure to the pathogen in the trial population? What is the functionally pertinent immune mechanism to measure – IFNg spot forming cell frequency? Tetramer-positive cell frequency for immunodominant epitopes? Transcriptomic biosignatures derived from NHP models or from human challenge models? Neutralising or bactericidal antibodies? Are the biggest responses necessarily the best – what about immunopathogenic responses? The value and raison d’etre of this network would be to start to develop the relevant toolbox and a shared language that might advance elucidation and understanding of validated correlates. This is likely to encompass reliance on the types of approaches described above as well as development of new assays and technologies. In this, there will be synergistic overlap with networks looking at basic immunology, antigen discovery and, especially, systems vaccinology. Some solutions to these questions may cross between pathogens and even between human and veterinary trials, while others may be case-specific. The ultimate goal of this network will be to facilitate development of validated correlates that could be trusted by investigators and regulators, so speeding the vaccine development pipeline. Contact: Danny Altmann/Rosemary Boyton Imperial College [email protected] 7 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 6. Development of a trivalent vaccine for cattle papilloma, diarrhoea and rabies viruses Network Abstract: We aim to develop a trivalent vaccine for cattle papilloma, diarrhoea and rabies viruses. To achieve this goal, we plan to integrate an innovative multidisciplinary strategy that combines antigen design using a 3D structure-guided approach and the validation of the new antigenic proteins in vitro and in animal models with the evaluation of a range of adjuvants; formulation, stability and delivery systems tests for oral and systemic vaccine administration and the assessment of cattle vaccination and immunity impact on the transmission of these diseases. The multidisciplinary network brings together research groups in Mexico and the UK with expertise in quantitative field research of viral infections in cattle (National Centre of Multidisciplinary Research in Animal Microbiology, CENID-MA, Mexico); in vivo bovine models of vaccination (Department of Animal Health and Epidemiology, National Institute for Forestry, Agriculture and Livestock Research, Tamaulipas, Mexico); recombinant antigen production in plants and industrial fermentation processes of genetically modified organisms (Professional Centre of Biotechnology and Bioengineering of the National Polytechnic Institute, IPN, Mexico); government advisors and nationwide policy-makers for the sustainable development of the forestry, agriculture, and fishery sectors of Mexico (National Institute for Forestry, Agriculture and Livestock Research, INIFAP, Mexico City Mexico); one industrial partner with a proven record of R&D of viral vectors for vaccine delivery (Oxford Expression Technologies, OET, Oxford England); vaccine adjuvants (Adjuvant Bank Facility, the Jenner Institute, University of Oxford) and the WHO Vaccine Formulation Laboratory (Lausanne, Switzerland); mathematical models of epidemiology of vaccine preventable disease in cattle infections (Department of Veterinary Medicine, University of Cambridge, England) and structure-guided antigen design and overproduction in diverse expression systems (bacteria, yeast, baculovirus) (Oxford Brookes University, Oxford England). Importantly, ad hoc protocols for the expression and purification of selected protein antigens and authorisation by the appropriate regulatory bodies of the government of Mexico to conduct research studies in cattle are already available, setting the stage for the work outlined in this proposal. The research proposed can be completed within 60 months, as it is built on the previous work of the applicant on the structure-guided design of individual proteins and protein complexes and the complementary expertise and commitment of the collaborators in the named organisations. I omitted the names of the collaborators to keep this outline short but I would be happy to provide you with full names and contact details if needed. Contact: Victor M. Bolanos-Garcia Oxford Brookes University 8 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 7. Emerging infections – pathogen biology and evolution Network Abstract: Contact: 9 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 8. Formulation and stability (inc. cold chain), and modes of vaccine delivery Network Abstract: Maintaining the cold chain increases the cost of immunisation by 14% (WHO) and vaccine damage as a result of cold chain breakages costs human lives. This is especially relevant to mass vaccination programmes in developing countries with high ambient temperatures and lack of infrastructure to support a reliable cold-chain. Stabilisation of vaccines has been identified as one of the key technologies capable of transforming immunisation programmes in the 21st century. This network aims to bring together specialists to develop new technologies that reduce the requirement for cold chain logistics. There is also a need for needle-free vaccine delivery in order to optimise immune responses at mucosal surfaces and enable patient friendly administration without the need for trained medical professionals. This network will also aim to create capability to replace the requirement for injection mediated administration of vaccines. The ultimate scientific focus of this network merges the interrelated research areas of vaccine formulation and stability with vaccine delivery in order to enable the creation of platform technologies offering the formulation of stable vaccines for multiple administration routes. The scientific expertise underpinning this network is highly multidisciplinary and includes materials science, nanotechnology, structural stability, microbiology and immunology. Colleagues from industry, academia, regulatory bodies and clinical practice will collaborate on an open platform to achieve the aims of the network. Contact: Lorna Lancaster, University of Lincoln [email protected] 10 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 9. Human challenge models Network Abstract: Since the time of Edward Jenner, the UK has distinguished itself in volunteer challenges to prove vaccine efficacy. Such studies streamline vaccine development (doi:10.1038/nri2902), elucidate disease pathogenesis and allow mechanisms of protection to be discovered. They are particularly important where animal models do not exist or do not fully reflect human disease and when early events (during the disease prodrome) need to be studied; this cannot be done in observational studies. Volunteer challenge is especially useful for diseases that are sporadic or unpredictable in nature. The UK has an excellent legal and ethical environment in which to perform such experiments and is a global leader in this field. Further coordination and investment would greatly accelerate these studies, reducing commercial risks and facilitating vaccine and antimicrobial development. The list of pathogens with which it is (or has been) ethically and practically feasible to perform volunteer challenge includes Escherichia coli, Helicobacter pylori, Shigella, Salmonella typhoid 10.1093/cid/ciu078, pneumococcal and meningococcal carriage, helminths, tularaemia, , gonorrhoea, malaria, cholera, dengue, rhinovirus, influenza and RSV (PMID: 23174372; PMID: 27199398). Potential future challenge models include Zika virus and human coronaviruses (that cause common colds, but are homologous with MERS and SARS-coronaviruses). The UK has multiple research groups working mainly on enteric pathogens and respiratory pathogens. The preliminary list includes: • Imperial: Peter Openshaw, Sebastian Johnston, Chris Chiu, Robin Shattock, David Lewis (influenza, RSV, rhinovirus) and Bob Sinden (malaria, 10.1016/j.vaccine.2011.03.083) • Oxford: Andrew Pollard (Salmonella typhi), Adrian Hill (malaria), Helen McShane (tuberculosis/BCG) • Liverpool: Stephen Gordon (Streptococcus pneumoniae) • York: Paul Kaye (leishmania) • Nottingham: David Pritchard (hookworm), Jonathan Nguyen-Van-Tam (influenza) • Southampton: Tom Wilkinson (rhinovirus, RSV, influenza) Robert Read (Neisseria meningitides, B. pertussis). Each group has industrial links to vaccine/antimicrobial manufacturers including GSK, AstraZeneca (Medimmune) Janssen and smaller biotech/SMEs (e.g. hVivo, Mucosis BV, NL). The network might also include organisations that have an interest in vaccines (JCVI), public health (PHE and equivalents in devolved regions), assay standardisation (e.g. NIBSC), policy/public engagement (e.g. the British Society for Immunology, Society for General Microbiology), NIHR funded BRCs and other such bodies. The network should be linked to other sites in Europe and elsewhere that undertake work in this area (e.g. the US-based Controlled Human Infection Models (CHIM) consortium coordinated by PATH and The Emmes Corporation https://www.ghvap.org/Pages/default.aspx, NIH, NIAID, Bill and Melinda Gates Foundation, Johns Hopkins DOI: 10.1186/s12864-016-2777-0, the University of Rochester (John Traynor, Anne Falsey, USA), and Singapore (Annelies Wilder-Smith, 10.11622/smedj.2014114). Contact: Peter Openshaw Imperial College [email protected] 11 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 10. Immune responses to enteric vaccines (inc. underperformance of rotavirus vaccine) Network Abstract: Contact: 12 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 11. Immunogen design Network Abstract: Contact: 13 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 12. Network to define methodologies for early phase and pre-licensure impact of candidate vaccines on transmission of target infections (herd effects) Network Abstract: Vaccines are developed and licensed based on their direct effects (protection of recipient against target disease) Most vaccine programmes’ effectiveness depend heavily on indirect effects (impact on transmission of target disease from recipient to others) Although several groups are working in this area, using different approaches, there is no consensus as to how to evaluate such effects during the development of vaccines This network will bring together researchers using different approaches to this question both with respect to vaccines targeting respiratory tract and gastrointestinal infections including: Immunological, microbiological and transmission experiments in farm and laboratory animals Human challenge studies Human descriptive and experimental medicine studies, including interventional vaccine studies Dynamic transmission mathematical models Failure to develop this field may result in failure to recognise and develop vaccines with potential effectiveness at the population level, and conversely investment in vaccines which may have inadequate impact on transmission to be effective or cost effective. The network would permit investigators to apply their distinct approaches in concert to one or two specific areas (possibly a vaccine with known impact on transmission - for proof of principle) and demonstrate their complementarity in establishing/measuring potential for impact on transmission during the development phases of vaccines. Contact: Adam Finn [email protected] @adamhfinn skype adamfinn 14 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 13. In vivo animal models Network Abstract: Contact: 15 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 14. Iterative vaccine development for complex neglected intracellular pathogens Network Abstract: Scientific Problem: For several complex bacterial diseases we do not have sufficient understanding of the most effective protective immune mechanisms and this limits our ability to develop vaccines for humans and animals. Critical questions regarding immunity that need to be answered for these diseases are: Are immune pathways induced by natural infection sufficient to protect against subsequent disease? What regulates expression of effective immunity locally and systemically? Can non-natural immune mechanisms be engaged to limit or eliminate infection and disease? Novel Approach: Current approaches tend to be linear in nature i.e. identify a natural element of the immune response (antigen, antibody, cellular response), induce it by known vaccine mechanisms and test its capacity to alter disease in animal models. We propose an iterative approach focusing on developing an accurate working model of immunity by repeated integration of data from experimental medicine and animal models. While the experimental medicine provides the touchstone for relevance and for translation, the animal models provide the tool with which to test mechanism and immune pathways within the complexity of a vertebrate immune response. The integrated approach also incorporates in silico and in vitro approaches to further expand the model and to delineate molecular and cellular mechanisms. The iterative approach is something that proceeds in an uncoordinated way in the literature and within the scientific community. This Network call provides a unique opportunity to bring together individuals and promote free sharing of information within a protected environment. In this way both positive and negative results can be communicated rapidly and the working models being built for each of the complex disease can learn from the success and failures of the others. The network will also facilitate use of ‘omics activities with coordinated production of samples and the use of reproducible and fully delineated procedures discussed and designed following discussion and sharing of already generated data. Areas of focus: • Parallel experimental medicine and animal studies helps us understand what can be modelled • Focus on translating basic mechanisms into human experimental medicine, and back again • Mucosal v systemic immunity • Correlates of protection – CMI and humoral • Aerosol delivery • Pathogen challenge models/ Human challenge models • In vitro killing assays • Computational models • Capacity development for preparation of trial sites for phase I clinical trials and experimental medicine studies (GCLP training, assay qualification etc). Contact: Helen McShane, University of Oxford [email protected] 16 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 15. Structural vaccinology Network Abstract: Contact: 17 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 16. Successful vaccination against parasitic helminths: a global approach through targeting immunomodulators Network Abstract: Helminth infection remains highly prevalent in many low-to-middle income countries (>2 billion people infected worldwide), and causes a range of debilitating conditions across all age groups. In fact, 8/17 of the Neglected Tropical Diseases recognized by the WHO are caused by these parasites. They are also highly important from a veterinary parasite perspective, both in terms of zoonosis and livestock infections. Control is currently primarily achieved through mass drug administration. However, this induces little immunity against reinfection, does not reverse pathology, and is vulnerable to the development of drug resistance which is already prevalent in livestock parasites. Although they represent several diverse taxonomic groups, disease-relevant helminths induce common immune responses, with type 2 and immunoregulatory pathways predominating, coupled with suppression of host immunity to ensure long term parasite survival. We believe previous helminth vaccine attempts have failed because they (a) indiscriminately targeted abundant or highly immunogenic proteins (b) lack little mechanistic understanding what constitutes a protective immune response and (c) underestimate natural variation in response to immunisation and natural exposure, which ensures continued transmission by vaccine non-responders in the target population. However, the members of our network have led a conceptual advance in mouse model and veterinary parasites, whereby the neutralisation of parasite-derived immunomodulatory molecules unleashes the host immune response to enact parasite expulsion. There is a clear analogy to the transformation of cancer therapy by immunologicals which block tumour-derived immune suppression. We now wish to move this approach into human-relevant pathogens, and have assembled a network with strong expertise in each key area of host immunology and parasitology, including : parasite immunomodulatory molecules (both proteins and glycans), mouse and animal models of immunity, identification of protective mechanisms, innate responses to parasites, variation both in parasite antigens and in the host response to immunisation, human explants, human challenge models, adjuvants and antibodies, structural analysis and scientists active in endemic areas. Bringing together researchers with expertise in these fields will allow us to neutralise parasite (and host) immunomodulators in mouse models of human infection, in veterinary systems with real-world infections, and in new and relevant human models, building towards developing novel human anti-helminth vaccines. Through established links we will also collaborate with endemic viral and bacterial pathogenesis groups to assess the impact of helminth infection (and immunoregulation) on vaccines against these outbreak pathogens. Contact: 18 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 17. Systems Biology Network Network Abstract: This Network will develop and test novel approaches to the analysis of complex datasets to improve our understanding of vaccine-induced immunity, identify correlates of vaccine protection, and optimise vaccine dosing and scheduling. These data will include conventional disease and carriage endpoints, antibody levels, cellular responses, transcriptomics, proteomics and host genetics. In the first phase, this interdisciplinary Network will develop a standardised approach to the curation and interrogation of existing datasets from animal models, human challenge studies, and human and animal vaccine trials; and optimise these through pump priming projects. In the next phase, the Network will prospectively validate these new tools in animal and human vaccine studies Contact: Robert S Heyderman, University College London [email protected] 19 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 18. Understanding the human host: Impact of Maternal Immunisation on neonatal immunity and early-life vaccine responses Network Abstract: Maternal immunisation is a strategy to prevent neonatal infections through passive transfer of specific maternal antibody, induced via immunisation in pregnancy against vaccine-preventable diseases which could affect the infant or the pregnant woman. The principle has been tried and tested for tetanus, pertussis and influenza. Additional and novel candidate vaccines are now being considered, such as against Group B streptococcus, RSV and possibly CMV. A focus for development funding: The millennium goals 4 and 5 were not reached in the previous decade and neonatal mortality (death in the first 28 days of life) now makes up 40% of overall deaths in children under 5 years of age. Maternal and neonatal health therefore remains a focus of international investment in global health. The majority of the complications and deaths are infection related, followed by stillbirths/premature births, birth asphyxia and congenital abnormalities. The momentum to develop and implement maternal vaccines is increasing, given the expectation that this strategy can contribute significantly to lowering the rates of neonatal morbidity and mortality, plus possibly improve maternal health and reduce still births. However, genuine challenges remain, independent on which vaccines will be used. Added value of the network: This network of key stakeholders in the field of maternal and neonatal vaccination will be able to jointly address key scientific opportunities and challenges for implementing maternal vaccination in LMIC as well as in the UK/Europe. We will create the momentum for joint-up thinking between academic partners and industry, regulators, the WHO/Brighton collaborations and social scientists, all already deeply engaged in developing safe and effective vaccines for use in pregnancy. Between already identified interested parties- see below-, the network can address the following scientific areas: - Basic science exploring mechanisms of immune sensing through the placenta via exosomes and in depth understanding of transplacental antibody transfer - Role of the microbiome of mothers and infants for impacting on susceptibility to GBS and other pathogens and immune responses and human milk oligosaccharides and other factors in breastmilk - Systems Vaccinology studies of early innate signatures of EPI vaccines as predictors of correlates of protection and the impact of maternal antibody on such signatures, including on neonatal vaccines - Harmonisation serological assays for use in (GBS) vaccine trials - Clinical trials of vaccines given in pregnancy in both UK and The Gambia and other LMIC - International networks through organisations such as INMIS (International neonatal and maternal immunisation symposium), case definition initiatives like the Brighton Collaboration (GAIA), the WHO influenza initiative/maternal immunisation platforms - Vaccine acceptancy studies and evaluation of e-health tools such as the MatImms app Contact: Beate Kampmann, Imperial College London, [email protected] 20 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 19. Vaccines for chronic diseases Network Abstract: Contact: 21 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC 20. Mixing Infectious Disease, Inflammation and Vaccines (MIDIV): Effects of cochallenges on immune responses. Network Abstract: Real life situations, especially in developing countries, rarely present an opportunity for a vaccine to be the sole challenge to the immune system at any given time. There are some instances of co-infection where it is well known that one challenge will affect the response to another; HIV and TB for example. The synergy between influenza and pneumococcal infections in respiratory disease is well recognised, although poorly understood. Even less is known about pathogens from the developing world, where there is often a huge infectious disease burden in the population which would be the background upon which any vaccination program would need to be effective. LMI countries do not always have the sophisticated diagnostics required to assess the current infectious burden. Patient-specific factors that affect the dynamics of infection recovery and normal symptoms of infection such as age of patient, seasonal/diurnal timings of challenge, coincident stress responses will also increase the chances of unintended coincidental challenges. Modelling the dynamics of immune responses under co-challenge conditions will be a high data-volume and complex process ideally suited to a systems immunology approach. We believe that fitness to respond to vaccination is compromised by concurrent infections and/or by patient age/neuroendocrine/inflammatory factors. This network aims to better understand the interplay of immune co-challenges such that more personalised vaccine regimes become a reality and can be tailored to suit the environment in which they are deployed. Contact: Deborah Dunn-Walters University of Surrey 22 Version 5 – Last Updated 14:30 on 28-10-2016 | MRC